2-or 3-alkyl-2, 3-epithio-5alpha-androstan-17beta-ols and their 17-alkanoates, and production thereof



United States Patent 0 2- 0R 3-ALKYL-2,3-EPITHIO-5a-ANDROSTAN-17 3- OLSAND THEIR 17-ALKANOATES, AND PRO- DUCTION THEREOF Taichiro Korneno,Osaka, Japan, assignor to Shionogi & Co. Ltd., Osaka, Japan No Drawing.Filed Feb. 23, 1966, Ser. No. 529,210 2 Claims. (Cl. 260-2395) Thepresent invention relates to 2- or3-alkyl-2,3-epithio-Sa-androstan-l7B-ols and their 17-alkanoatesrepresented by either one of the following general formula:

O R R I I S21 and S (In) (Ib) H R H II R 3,341,523 Patented Sept. 12,1967 wherein R is a hydrogen atom or a lower alkanoyl group (e.g.formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl,trimethylacetyl, capr-oyl, t-butylacetyl, enanthoyl, capryloyl), R is alower aikyl group (e.g. methyl, ethyl, propyl) and the ripple mark (5)represents a generic indication of aand ,B-configurations, and production thereof.

A basic object of the present invention is to embody the2-a1kyl-2,3-epithio-steroids (Ia) and the 3-alkyl-2,3-

10 epithio-steroids (Ib). Another object of this invention is to embodythe 2-alky1-2,3-epithio-steroids (Ia) and the3-alkyl-2,3-epithio-steriods (Ib) having peculiar hormonic activity. Afurther object of the invention is to embody (Ia) and the3-alkyl-2,3-epithio-steriods (Ib). These and other objects will beapparent to those conversant with the art to which the present inventionpertains from the subsequent description.

0R 1 a process for preparing the 2-a1kyl-2,3-epithio-steroids a 5 20 Thesubstantial conversion in the process of the present invention isrepresented by the following scheme showing only the A ring of thesteroid skeleton:

(Ila) A.

wherein X is a halogen atom (e.g. chlorine, bromine,

iodine), a lower alkanoyloxy group (e.g. acetyloxy, propionyloxy,butyryloxy), a lower alkanesulfonyloxy group (e.g. methanesulfonyloxy,ethanesulfonyloxy), a benzenesulfonyloxy group or a loweralkylbenzenesulfonyloxy group (e.g. toluenesulfonyloxy) and R has thesame significance as designated above.

Examples of the 2-alkyl-A -steroid (Ila) and the 3-alkyl-A -steroid(IIb) available as the starting materials in the present inventioninclude 2-methyl-5a-androst-2en- 17,8-ol and its l7-formate, acetate,propionate, butyrate, isobutyrate, valerate, isovalerate,trimethylacetate, caproate, t-butylacetate, enanthate, caprylate,3-methyl-5aandrost-2-en-l7B-ol and its l7-acetate, propionate, butyrate,isobutyrate, valerate, trimethylacetate, Z-ethyl-Suandrost-2-en-17B-oland its l7-acetate, propionate, 3-ethyl- 5a-androst-2-en-l75-ol and its17-acetate, propionate, Z-PIOpYi-Swandl'OSt-Z-Bll-175-01 and its17-acetate, 3-propyl-Sa-androst-Z-en-l7fl-ol and its l7-formate,acetate, propionate, etc.

According to the present invention, the starting 2- or3-alkyl-5a-androst-2-en-175-01 or its lower alkanoate (II) is firstsubjected to epoxy linkage-formation. The epoxy linkage-formation may beeffected by treatment with an epoxydizing agent such as a peracid (e.g.perbenzoic acid, rnonoperphthalic acid, peracetic acid,trifiuoroperacetic acid, m-chloroperbenzoic acid), ozone or chromiumtrioxide, or a combination of a halogenating agent such as ahypohalogenic acid (e.g. hypochlorous acid), an N- halocarbonamide ordicarbonimide (e.g. N-bromoacetamide (N-bromosuccinimide,N-iodosuccinimide, N-chlorophthalimide), a halonium compound (e.g.iodine and silver acetate, bromine and silver benzoate, bromine andmethanol) or the like and a base (e.g. alumina, pyridine, sodiumbicarbonate, potassium carbonate, potassium acetate, sodium methoxide,potassium hydroxide). Treatment with the epoxydizing agent may becarried out in an inert solvent (e.g. benzene, ether, dichloromethane,chloroform) at a temperature from about -10 C. to the boiling point ofthe solvent used within a period from about 1 to about 150 hours.Treatment with the combination of a halogenating agent and a base may becarried out in one step wherein the introduction of a halogen atom isfollowed by spontaneous dehydrohalogenation to form an epoxy linkage orin two steps wherein the intermediarily produced halohydrin is isolatedprior to the subsequent dehydrohalogenation with a base. Thehalogenation may be carried out in an inert solvent (e.g. water,methanol, acetic acid, chloroform, dichlorornethane, carbontetrachloride, ether, benzene) at a temperature from about 0 C. to theboiling point of the solvent used within about 10 hours, optionally inthe presence of a catalyst such as an acid (e.g. perchloric acid, aceticacid). The dehydrohalogenation may be carried out in an inert solvent(e.g. water, methanol, ethanol, isopropanol, acetone) at a temperaturefrom room temperature (10 to 20 C.) to the boiling point of the solventused within about 24 hours. The halogenation followed by the spontaneousdehydrohalogenation may be carried out by treatment with a halogenatingagent in the presence of a base, preferably an organic base (e.g.pyridine). The configuration of the epoxy linkage in the resultingproduct is associated with the kind of the starting 2- or 3-alkyl-Asteroid (II) and the adopted procedure. For instance, the reaction ofthe 2-alkyl-A -steroid (Hat) with the combination of a halogenatingagent and a base affords the 2-alkyl- 2/3-3fl-epoxy-steroid (1111:),while that with a peracid gives the 2-alkyl-2u,3ot-epoxy-steroid(IIIa"). Further, for instance, the reaction of the 3-alkyl-A -steroid(IIb) with the combination of a halogenating agent and a base affordsthe 3-alkyl-2B,3B-epoxy-steroid (IIIb) and the 3--alkyl-2a,3u-epoxy-steroid (IIIb"), while that with a peracid gives the3-alkyl-2a,3u-epoxy-steroid (11112).

The 2- or 3-alkyl-2,3-epoxy-steroid (III) is then subjected to epoxylinkage-fission. The epoxy linkage-fission may be effected by reactingthe 2- or 3-alkyl-2,3-epoxysteroid (III) substantially with thiocyanicacid. Practically, the reaction is carried out by treating the 2- or 3-alkyl-2,3-epoxy-steroid (III) with thiocyanic acid or its salt (e.g.sodium thiocyanate) in an inert solvent (e.g. water, methanol, acetone,ether, tetrahydrofuran, dioxane, chloroform, dichloromethane) at atemperature from about 0 C. to the boiling point of the solvent usedwithin about 5 days, if required, in the presence of catalytic influenceof an acid (e.g. acetic acid) or a base (e.g. pyridine).

The resultant thiocyanatohydrin (IV) is then subjected to epithiolinkage-formation as it is or after converting the hydroxyl group at the2- or 3-position into a halogen atom or an acyloxy group (the termacyloxy being intended to mean lower alkanoyloxy, loweralkanesulfonyloxy, benzenesulfonyloxy and lower alkylbenzenesulfonyloxy,inclusively). For the previous conversion of the hydroxyl group into ahalogen atom, the thiocyanatohydrin (IV) may be treated in a per seconventional halogenation procedure. The conversion of the hydroxylgroup into the acyloxy group may be performed by treating thethiocyanatohydrin (IV) in a per se conventional acylation procedure. Theepithio linkage-formation may be effected by reacting the freethiocyanatohydrin (IV) or the thiocyanato halide or acylatedthiocyanatohydrin (V) with a basic agent in an inert solvent (e.g.methanol, ethanol, propanol, benzene, toluene, petroleum ether,diglyme). As the basic agent, there may be employed an optional basehaving weak to strong basicity such as alumina, pyridine, sodiumbicarbonate, potassium carbonate, sodium acetate, sodium methoxide orpotassium hydroxide. It is generally preferred to carry out the reactionat a relatively mild condition, i.e. at a temperature not higher than C.within about 5 days.

In the course of the above conversion, the hydroxyl group or the loweralkanoyloxy group at the 17-position may be altered each other,naturally or optionally. The optional conversion of the hydroxyl groupinto a lower alkanoyloxy group may be carried out by a per seconventional procedure.

Examples of the resulting 2-alkyl-2,3-epithio-steroid (Ia) and the3-alkyl-2,3-epithio-steriod (Ib) include 213-methyl-2ot,3a-epithi-O-Su-andrQstan-17B 01 and its 17- formate, acetate,propionate, butyrate, isobutyrate, valerate, isovalerate,trimethylacetate, carproate, t-butylacetate, enanthate, caprylate,Za-methyl-Zfl,3B-epithio-5w-androstan-l7/8-ol and its 17-acetate,propionate, butyrate, valerate, trimethylacetate, t butylacetate,enanthane, 3,8- methyl-2a,3a-epithio-Sa-androstan-175-01 and its17-acetate, propionate, butyrate, isobutyrate, valerate,trimethylacetate, 3a-methyl-2B,3B-epithio-h-androstan-175-01 and its17-acetate, propionate, 2a-ethyl-2fl,3IB-epithiO-Sa-androstan-17B-ol andits 17-acetate, 3,8-ethyl-2a,3a-epithio- 5w-androstan-17fl-ol and its17-acetate, 3a-ethyl-2B,3B- epithiO-Sa-androstan-176-01 and its17-acetate, 2 3-propyl- 20,3u-epithio-Sa-androstan-l7B-ol and its17-acetate, 2apropyl-Zfl,3 8-epithio-5ot-androstan-17 6-01 and its17-acetate, 3 3-propyl-2a,3w-epithiO-Sa-andmstan-175-01 and itsl7-formate, acetate, propionate, 3ot-propyl-2fi,3/9-epithio-5ot-androstan-17B-ol and its 17-acetate, etc.

The 2-alkyl-2,3-epithio-steroid (Ia) and the 3-alkyl-2,3-epithio-steroid (Ib) prepared by the present process possess peculiarhormonic activity. Thus, they can produce potent myotropic andandrogenic activities with a favorable myotropic/androgenic ratio.Accordingly, they are useful as anabolic agents. It is especiallynotable that the 2-alkyl-2,3-epithio-steroid (Ia) and the3-alkyl-2,3-epithiosteriod (Ib) are markedly less potent than thecorresponding 2- or 3-desalkyl-2,3-epithio-steroid in anti-estrogenicactivity, which should be rather considered as a side effect foranabolic agents. For instance, the anti-estrogenic activity of2B-methyl-2a,3a-epithio-Su-andl'ostan-17,8-ol (Ia: R=CH ([3), R'=H) isabout that of 2a,3oc-epithio- 5a-androstran-l7fl-ol in the test usingmice. Accordingly, the 2-alkyl-2,B-epithio-steroid (Ia) and the 3-alkyl-2,3- epithio-steroid (lb) of the present invention are anabolicagents having less side effect. It is further notable that the compounds(Ia or Ib) having a lower alkanoyloxy group at the 17-position show theprolonged activities.

The 2-alkyl-2,3-epithio-steroid (Ia) and the 3-alkyl-2,3-epithio-steroid (Ib) of the present invention are used in medicinesolely or in combination or in preparation in conjunction with a solidor liquid pharmaceutical excipient. The preparations are prepared by assuch known methods, for example, with the use of pharmaceutical organicor inorganic excipients suitable lfOl" parenteral, enteral or localadministration. Suitable excipients are substances that do not reactwith the products of the present invention such, for example, as water,vegetable oils, benzyl alcohols, polyethylene glycols, gelatin, lactose,starches, magnesium stearate, talc, white petroleum jelly, isopropylmyristate or other known pharmaceutical ex-cipients. There areespecially made preparation for parenteral administration, preferablysolutions, above all oily or aqueous solutions, furthermore suspensions,emulsions or implants; for enteral administration there are similarlyalso made tablets or dragees, and for local administration alsoointments or creams. If desired, auxiliaries may he added thereto, suchas preserving, stabilizing, wetting or emulsifying agents, salts forregulating the osmotic pressure, or buffers. They may also contain othertherapeutically useful substances. The preparations are obtained in thecustomary way, The content of active compound in these preparations,such as of a tablet or an ampoule, is preferably 0.1 to 200 mg. or 0.03to 60%. The average dose is preferably 5 to 100 rug/week.

The following examples represent presently-preferred embodiments of thepresent invention, but it is to be understood that the examples aregiven by way of illustration only and not of limitation.

Example I OCOCH OH on, on, I

(C) CHaCOO OCOOH;

NCS-- (A) Preparation of Za-methyl-2;3,3/3-ep0xy-5a-andr0-stan-17fl-0l.-To a solution of 2-methyl-5a-androst-2-en- 178-ol-17-acetate [Ringold et al.: J. Am. Chem. Soc., 81,

427 (1959)] (979 mg.) in dioxane (12 ml.), there are added water (3ml.), N-bromoacetamide (613 mg.) and 60% perchloric acid (0.42 ml.) inorder, and the resultant mixture is stirred at room temperature for 1.5hours. After addition of a mixture of ice and water ml.), theprecipitate is collected by filtration, Washed with water, dried andcrystallized from hexane to give 2a-methyl-3abromo-5u-androstane-2fi,178-diol 17-acetate (490 mg.) as crystals melting at 161 to 163 C. [a]+54.6i2 (c. '=0.961, CHCl IR: yggy cmf 3558,3510, 3406, 1739, 1712,1275, 1263, 1248, 960, 895. vggggcmr 3614, 3485, 1740, 1249, 1034 IR:112:1? cmf 3464, 3410, 1051, 840, 800

(B) Preparation of2a-methyl-a-thiacyanatO-Sa-ana'msZane-2fi,17,B-di0l.To a solution of2a-methyl-2B,3B- epoxy-5a-androstan-175-01 (1.987 g.) in dichloromethane(50 ml.), there is added a solution of thiocyanic acid prepared frompotassium thiocyanate (10 g), phosphoric acid (15 g.) and ether (40ml.), and the resultant mixture is allowed to stand at room temperatureovernight. The reaction mixture is combined with chloroform, washed withwater, sodium carbonate solution and water in order, dried overanhydrous sodium sulfate and concentrated under reduced pressure. Theresidue is crystallized from acetone to give2a-methyl-3a-thiocyanato-5aandrostane-2B,17B-diol (1.585 g.) as crystals"melting at 218 to 220 C. [a] +119.0i2

(c.=1.066, CHCl MeOH (4:1)) IR: All? emf: 3480, 3372, 2155, 1043 (C)Preparation of 2a-methyl-3a-thi0cyanatm5wandrostone-25,17,8-diol2,17-diacetate.-To a solution of2amethyl-3a-thiocyanato-5a-androstane-2/9,17B-diol (1.311 g.) in amixture of acetic acid (25 ml.) and acetic anhydride (4 ml.), there isadded p-toluenesulfonic acid mg.), and the resultant mixture is allowedto stand at room temperature overnight. Thereaction mixture is pouredinto a mixture of ice and water. The precipitate is collected byfiltration, washed with water, dried and crystallized from a mixture ofacetone and hexane to give2a-methyl-3a-thiocyanato-Sa-andmstam-ZB,17,8-dio1 2,17- diacetate (1.292g.) as crystals melting at 1164 to 166 C. [cc] +81.Oi2 (c.:= 0.974, CHCIIR: 11, 131? cmr z 2160, 1736, 1255, 1242, 1037 (D) Preparation of2,8-methyl-2a,3a-epilhi0'5a-andr0- stan-17fi-0l.-To a solution ofpotassium hydroxide (935 mg.) in ethanol (40 ml.), there is added2a-methyl-3athiocyanato-Sa-androstane-ZB,17 3-diol 2,17-diacetate (927mg), and the resulting mixture is refluxed for 2 hours. After removal ofethanol by distillation, water is added thereto. The resultant mixtureis extracted with dichloromethane. The extract is crystallized from amixture of ace tone and hexane and recrystallized from aqueous methanolto give Zfl-methyl-Za,3a-epithio-5oz-androstan-17fl-ol (325 mg.) ascrystals melting at 151.5 to 153.5 C. [a] +27.5:2 (c.=1.213,, CHCl IR:vfilti? cmf z 3322, 1053 1038, 9.59

drstan-17B-ol (115 mg.) is dissolved in a mixture of pyridine (4 m1.)and acetic anhydride (1 ml.), and the resulting mixture is allowed tostand at room temperature overnight. The reaction product iscrystallized from aqueous acetone to give 28-rnethyl-2a,3a-epithiQ-Sa-androstan-l7/3-ol l7-acet-ate as crystalsmelting at 142.5 to 144.5 c. [a] iZ (c.=1.111, (31101,

IR: page ant- 1731, 1254, 1049, 104.1, 1023, 956

In the similar manner, treatments of2B-methyl-2a,3aepithio-Sa-androstan-l713-01 with propionic anhydride inaqueous potassium carbonate solution or pyridine, butyric anhydride inpyridine, valeric anhydride in trimethylamine, trimethylacetyl chloridein pyridine and enanthyl bromide in pyridine afford respectively thecorresponding 12-propionate, butyrate, valerate, trimethylacetate andenanthate.

(F) Preparation of Zfl-methyI-ZOLJa-epithiO-Sa-andmstan-17,B-0l.-To asolution of 2 -methy1-3a-thiocyanato- Sa-aHdIOStEIHC-ZB,17,3-(1101 (289mg.) in dioxane (5 ml.), there is added a solution of potassiumhydroxide (0.5 g.) in 90% methanol ml.), and the resultant mixture isstirred at room temperature (10 to 20 C.) overnight. The reactionmixture is concentrated under reduced pressure, diluted with water andextracted with dichloromethane. The extract is crystallized from aqueousmethanol to give 2B-methyl-2a,3a-epithio-5a-androstan-17,8-01 ascrystals melting at 151.5 to 153.5 C.

Example 2 ?COCH3 OCOCH ()COCH3 OCOCHS lfi 1 l (0) NC! CHQSOQO 1'1 2/ alOIH ?COC1'I3 011 U l P (E) S S (A) Preparation of2,8-methy[-2a,3a-epoxy-5ot-andr0- stan-J 7B-0l ]7-acetate.T-o a solutionof Z-methyl-Sa-androst-2-en-l7fi-ol 17-acetate (1.935 g.) in a mixtureof dichloromethane and ether (1:1) (40 ml.), there is added a solutionof monoperphthalic acid (1.635 g.) in ether ml.), and the resultantmixture is allowed to stand at 0 C. overnight. The reaction product iscrystallized from acetone to give2fl-methyl-2a,3a-epoxy-5a-androstan-175-01 l7-acetate (1.601 g.) ascrystals melting at 208 to 210 C. [u] +10.6i2 (c.=1.073, CHCl IR: V132crnf z 1732, 124-2, 1043, 1031, 919, 899, 809,

(B) Preparation of 2a-methyl-Zfl-thi0cyana't0-5a-andr0- smite-3a,]7fi-di0l Z 7-acetate.-To a solution of Zfl-methyl-271,3a-epoxy-5a-androstan-175-01 17-acetate (1.461 g.) indichloromethane (10 ml.), there is added a solution of thiocyanic acidprepared from potassium thiocyanate (7 g.), phosphoric acid (11 g.) andether (30 ml.), and the resulting mixture is allowed to stand at roomtemperature overnight. The reaction product is crystallized from amixture of acetone and hexane to give 2a-methyl-2/ithiocyanato 5aandrostane 3a,17/3 diol 17 -acetate (1.272 g.) as crystals melting at183 to 184 C.

IR: 115,31? cmf z 3144, 2164, 1735, 1249, 1049, 1013, 1026 (C)Preparation ofZa-m'ethyI-2,B-thiOc'yanaIO-Sa-methanesulfonyl0xy-5a-andr0stan-17,8-0117-acetate.To a solution of 2a-methyl-Zp-thiocyanato-Su-androstane-3a,176- diol 17-acetate (580 mg.) in pyridine (12 ml.), there is addedmethanesulfonyl chloride (800 ml.) under cooling with ice, and theresulting mixture is allowed to stand at 0 C. overnight. The reactionmixture is poured into a mixture of ice and water and extracted withether. The ether extract is washed with 10% hydrochloric acid, 'water,10% sodium carbonate solution and water in order, dried over anhydroussodium sulfate and the ether evaporated by distillation to give2wmethyl-2B-thiocyanato-3tit-methanesulfonyloxy-Sa-androstan-17(3-0117-acetate ('689 mg.).

IR: 1351 4 emf 2171, 1737, 1231, 1186, 1034, 896

(D) Preparation of Za-methyl-ZB,3fl-epithio-5a-andr0- stan-17-0l.To asolution of 2a-methyl-2fl-thiocyanato- 3a methanesulfonyloxy 5aandrostan 17B -ol 17- acetate (689 mg.) in dioxane (10 ml.), there isadded a solution of potassium hydroxide (911 mg.) in methanol (22 ml.),and the resultant mixture is stirred at room temperaure overnight. Afterconcentration under reduced pressure, water is added thereto. Theresultant mixture is extracted with dichloromethane. The extract iscrystallized from a mixture of acetone and hexane to give Zea-methyl-2fl,3B-epithio-5u-androstan-175-01 (250 mg.) as crystals melting at to157 C. [a] +47.5:2 (c.=1.046, CHCl IR: 1123i? omf t 3470, 1062, 1004,988, 938

(B) Preparation of 2a-methyl-2fl,3fl-epithio-5a-andr0- Stan-1 7fl-0l17-acletate. A mixture of 2a-Inethy1-2B,3fiepithio-5a-androstan-175-01220 mg.), pyridine (3 ml.) and acetic anhydride (1 ml.) is allowed tostand at room temperature overnight. The reaction product iscrystallized from a mixture of acetone and hexane to give 20:-methyl-2,8,3p-epithio-5a-androstan-175-01 17-acetate mg.) as crystalsmelting at 147 to 149 C.

[u]- +27.5i2 (c.=0.969, 0110,) IR: 1.5 1 cm.' 1730, 1250, 1047, 1026,914.

(F) Preparation of 2a-methyl-2/3,3,B-epithi0-5a-andr0- stan-17fl-ol.To asolution of Za-methyI-Zp-thiocyanato- 5a-androstane-3a,1773-diol17-acetate (351 mg.) in dioxane (15 ml.), there is added a solution ofpotassium hydroxide (0.5 g.) in methanol (10 ml.), and the resultingmixture is refluxed for 30 minutes. The reaction mixture is concentratedunder reduced pressure and then extracted with chloroform. The extractis crystallized from a mixture of acetone and hexane to give2a-methyl-2fl,3 8-epithio-5aandrostan-17001 as crystals melting at 155to 157 C.

(G) Preparation of 2a-methyl-2B,3fl-epithio-Sa-androstart-ml17-acetate.A solution of2a-methyl-2B-thiocyanato-3a-methanesulfonyloXy-5tit-androstan 17 6-0117- acetate (212 mg.) and potassium carbonate (250 mg.) indiethyleneglycol dimethyl ether (20 ml.) is stirred at room temperature(10 to 20 C.) overnight. The reaction mixture is diluted with water. Theprecipitated crystals are collected by filtration and recrystallizedfrom a mixture of acetone and hexane to give2a-methyl-2;3,3B-epithio-5a-androstan-17fl-ol 17-acetate as crystalsmelting at 147 to 149 C.

Example 3 0000113 OH (\Ii 1 f I (A) O on K 0113- l ii 1':

fin

0000113 000011, i j I I 3 O N08 CHa-- 1 X t r: CH3 it n o l( oooorn 0HCHaSO20\ I NOS I F OCOCHa s? CH3 (A) Preparation of3a-methyl-2fl,3;8-ep0xy-5a androszan-17/8-ol.-To a solution of3-methyl-5a-androst-2-en- 176-01 17-acetate [Pelc: Collect. czecho.chem. Comm., 25, 1624 (1960)] (6.858 g.) in a mixture of dioxane (60ml.) and water (17 ml.), there are added N-bromoacetamide (4.3 g.) and60% perchloric acid (1.4 ml.), and the resulting mixture is stirredunder cooling with ice for 30 minutes. After addition of a large amountof water, the precipitate is collected by filtration, washed with water,dried and treated with cold ether to separate an ethersoluble portionand an ether-insoluble portion. The soluble portion (6.854 g.) isrefluxed with potassium hydroxide (6.8 g.) in isopropanol (120 ml.) for1 hour. The reaction mixture is poured into a mixture of ice and waterand extracted with ether. The extract is dissolved in a mixture ofpetroleum ether and benzene (1:1) and chromatographed on Florisil (114g.). The eluates with benzene and with benzene-dichloromethane(95:5-75z25 are combined together and crystallized from ether and then amixture of acetone and hexane to give 3a-methyl-2fl,3 3-epoxy 50:-

androstan-17B-ol (1.265 g.) as crystals. melting at 189.5 to 192.5 C.[a] +46.5i2 (c.=1.014, CHCl IR: 11ml? cm. 3398, 1083, 1066, 1059, 1040,1028, 932, 905, 851, 840, 786, 698

IR: 1153i? cm. 1731, 1253, 1050, 1035, 936, 913, 891, 847, 704

(C) Preparation of 3fi-methyl-3a-thiacyanato 5a andr0stane-2/3J7B-di0l17-alcetate.-To a solution of 3amethyl-ZB,3fl-epoxy-5a-androstan-175-0117-acetate (1.509 g.) in dichloromethane (7.5 ml.), there is added asolution of thiocyanic acid prepared from potassium thiocyanate (7.5g.), phosphoric acid (11.3 g.) and ether (8 ml.), and the resultingmixture is allowed to stand at room temperature overnight. The reactionproduct is crystallized from a mixture of acetone and hexane to giveBfi-methyl-Ba-thiocyanatoa-andrQstane-ZB,17,3-diol 17- acetate (1.395g.) as crystals melting at 1.61 to 162.5" C. [a] +54-.9i2 (c.=1.000,CHCl IR: vfifii? cmf z 3516, 2156, 1719, 1273,1043 (D) Preparation of3,6-methyZ-ZB-methanesulfonyloxyoathi0cyanlo-5a-andr0stan-17,8-0!17-acerate.To a solution of3,B-methyl-Ba-thiocyanato-5a-andIOstane-Zfl,17pdiol 17-acetate (1.598g.) in pyridine (16 ml.), there is added methanesulfonyl chloride (2ml.) while cooling with ice, and the resulting mixture is allowed tostand at 0 C. for 8 days. The reaction mixture is poured into a mixtureof ice and water and extracted with ether. The ether extract iswashedwith water, 10% hydrochloric acid, Water, 10% sodium carbonatesolution and water in order, dried over anhydrous sodium sulfate andconcentrated. The residue is crystallized from a mixture of ether andpetroleum ether and recrystallized from a mixture of acetone and hexaneto give 3 fi-methyl-Zfl-methanesulfonyloxy-3a-thiocyanato 5a androstan17,5 01 17 acetate (1.056 g.) as crystals melting at 124 to 126 C. [a]+46.2:2 (c.=1.023, CHCl IR: page 0111- 2133, 1727, 1253, 1177, 1046,1039, 956, 921, 896, 373, 312

(B) Preparation of 3,8-methyl-2a,3a-ep.ithio-Sa-androstan-I7fi-0L-T0 asolution of 3p-methyl-2fi-rnethanesulfonyIoxy-3a-thiocyanato-5a-androstan-17,6-ol 17 acetate (1.056 g.) in dioxane (30ml.), there is added a solution of potassium hydroxide 1.1 g.) inmethanol (23 ml.), and the resulting mixture is stirred for 2.5 hours.After addition of water (5 ml.), stirring is continued for 20 hours. Thereaction mixture is combined with Water and extracted with ether. Theextract (700 mg.) is crystallized from a mixture of acetone and hexaneto give 3,8-methyl 2ct,3ot-CPlthiO-Soc-fifldIOSt311-17fl-0i (510 mg.) ascrystals melting at 126 to 128 C. [a] +26.Z- :2 (c.=1.075, CHCl IR:1,251, cmf 3258, 1082, 1051, 1029, 1011, 990, 959

(F) Preparation of 3/3-merhyl-2a,3a-epilhio-5a-anarostart-1750i17-acetaze.3/3 methyl-2a,3wepithiO-Sa-androstan-17 3-ol (128 mg.) isacetylated with. pyridine (0.5 ml.) and acetate anhydride (0.25 ml.).The reaction product is crystallized from acetone to give3/3-.methyl-2a,3aepithio-5a-androstan-l75-01 17-acetate as crystalsmelting 11 at 138.5 to 140.5 c. [a] +2O.2i2 c= -1.074,

CHCl

IR: taxi emf: 1734, 1251, 1046, 1032, 955, 906, 895

In the similar manner, treatments of3p-methyl-2a,3aepithio-5a-androstan-175-01 with propionic anhydride inaqueous sodium hydroxide solution of pyridine, butyric anhydride inpyridine, Valerie anhydride in pryridine or triethylamine,trimethylacetyl chloride in pyridine and enanthyl bromide in pyridineafford respectively the corresponding 17-propionate, butyrate, valerate,trimethylacetate and enanthate.

(G) Preparation of 3fl-methyl-2a,3a-epithi0-5a-andr0- stan-17l3-0L-To asolution of 3fl-methyl-3a-thiocyanato- 5a-androstane-2/3,17fi-diol17-acetate (432 mg.) in dioxane (20 ml), there is added a solution ofpotassium hydroxide (0.5 g.) in 90% methanol (15 m1.), and the resultingmixture is stirred at room temperature to 20 C.) for 2 days. Afteraddition of water, the reaction mixture is extracted withdichloromethane. The extract is crystallized from a mixture of acetoneand hexane to give 3fi-methyl-2a,3a-e ithio-Su-andmstan-17B 01 ascrystals, melting at 126 to 128 C.

Example 4 000113 on ()3 l (A) c 'r I moons on CHaCOO (E) Nos I orn 011(A) Preparation of 3a methyI-Z5,3,8-ep0xy-5a-androv stan-Ufl-aL-As inExample 3(A), 3a-methyl-2B,3 8-

methyl-3a-thiocyanato-5a-andrOstane-ZB,17/3-diol l7-acetate mg),pyridine (0.5 ml.) and acetic anhydride (0.25 ml. is allowed to stand atroom temperature for 48 hours. The reaction product is crystallized froma mixture of acetone and hexane to give 3 8-methyl-3a-thi0cyanatO-Sa-andrOstane-Zfi,17,6-diol, 2,17-diacetate as crystals melting at209.5 to 210.5 C. (OL]D23'5 +58.0i2 (c.=0.848, CHCl IR: 1123? cmr z2150, 1734, 1225, 1039, 1025 (B) Preparation of3fl-methyl-2a,3a-epithio-Sa-androstan-17fi-0l.To a solution of potassiumhydroxide (0.3 g.) in 90% ethanol (10 ml.), there is added 3B-methyl-3a-thiocyanato-5a-androstane-2,8,17fi-di0l 2,17-diacetate mg.) and theresultant mixture is refluxed for 2 hours. After removal of ethanol, theresulting product is combined with Water and extracted withdichloromethane. The extract is crystalized from a mixture of acetoneand hexane to give 3 8-methyl-2a,3a-epithio-Sa-androstan-Ufl- 01 ascrystals melting at 126 to 128 C.

Example 5 O COCHa OCOCHa (C) NCS(:\

it o 3 y PG) OCOCHa oH D cr-raooo J s\ l i CH3 H CH3 H 000cm i i s o'rra 1'1 (A) Preparation ofSfl-methyl-Za,3a-epoxy-5ot-androstan-17,8-0l.-To a solution of3-methyl-5a-androst-Z-en- 17;9-ol 17-acetate (6.858 g.) in a mixture ofdioxane (60 ml.) and Water (17 ml), there are added N-bromoacetamide(4.3 g.) and 60% perchloric acid (1.4 ml.), and the resulting mixture isstirred under cooling with ice for 30 IR: ufifii'f (MIL i 3495, 1085,1065, 1055, 1048, 1028, 960, 875, 809, 800

(B) Preparation of 3/8-methyl-2a,3ot-epoxy-5a-androstan-UB-ol17-acetate.-A mixture of 3fi-methyl-2a,3aepoxy-5a-androstan-176-01,pyridine and acetic anhydride is allowed to stand at room temperatureovernight. The reaction product is crystallized from hexane to give 36-methyl-2a,3zx-epoxy-5a-androstan-175-01 17-acetate as crystals meltingat 134 to 136 C. [111 +22.1i2 (c.=0.989, CHCl IR: 3.1 ant- 1739, 1252,1238, 1044, 1035, 959, 895, 875, 343, 812, 303

(C) Preparation of 3,8-methyZ-ZB-thiocyanato-Soc-androstane-3a,17B-'di0l]7-acetate.--To a solution of 35- rnethyl 20:,300 epoxy 5aandrostan-l75-ol 17-acetate (1.977 g.) in dichloromethane (10 ml.),there is added a solution of thiocyanic acid (10 ml.) prepared frompotassium thiocyanate (10 g.), phosphoric acid (15.5 g.) and ether (10ml.), and the resultant mixture is allowed to stand at room temperaturefor 2 days. The reaction mixture is extracted with chloroform. Theextract is crystallized from a mixture of acetone and hexane to give3/3- methyl 2B thiocyanato 5a-androstane-3a,17;9diol 17- acetate (2.05g.) as crystals melting at 168 to 170 C. [a] |55.1i2 (c.=0'.970, CHCIIR: 1113i? cmf z 3496, 3390, 3198, 2172, 1713, 1278, 1265, 1047, 1035(D) Preparation of .ifi-methyl-Zfl thiocyanato-jocandr0stane-3a,]7/8-diol 3,1 7-dz'acetate.-To a solution of 3/3-methyl-Zfl-thiocyanato-Sa-androstane-Ba,17B-dio1 17-acetate (1.802 g.)in acetic acid ml.), there are added acetic anhydride (9 ml.) andp-toluenesulfonic acid (400 mg), and the resulting mixture is allowed tostand at room temperature overnight. After addition of Water, theprecipitate is collected by filtration, Washed with water, dried andcrystallized from a mixture of acetone and hexane to give3,8-methyl-2fl-thiocyanato-5ot-androstane- 3a,l7,B-diol 3,17-diacetate(1.900 g.) as crystals melting at 177 to 178.5 C. [a] +72.5 (c.=1.077,CHCI3).

IR: viii? cm.- 2164, 1730, 1251 (E) Preparation 073rz-methyl-2B,3B-epithio-Sa-androstart-1 7fl-0l. A mixture of3fi-methyl-ZB-thiocyanate-5aandrostane-3a,17fi-diol 3,17-diacetate 1.900g.) and potassiurn hydroxide (2.0 g.) in ethanol (70 ml.) is refluxedfor 1 hour. The reaction mixture is combined with water and extractedwith dichloromethane. The extra-ct is chromatographed on Florisil. Theobtained crude product is crystallized from a mixture of acetone andhexane to give 3a-rnethyl-ZB,3,8-epithio-5a-androstan-17fi-ol (736 mg.)as crystals melting at 125 to 127 C.

[a] +46.5:t2 (c.=1.065, CHCl IR: 111113;? cmh z 3330, 1081, 1062, 1035,1014, 995, 961, 929

(F) Preparation of 3a-methyl-Zfl,3 3-epithi0-5a-andrm stun-1 7l3-ol J 7acetate.-3a-methyl-ZflflB-epithiQ-Stx-androstan-l7 3-ol (141 mg.) isacetylated with pyridine (0.5 ml.) and acetic anhydride (0.2 ml.). Thereaction product is crystallized from a mixture of acetone and hexane togive 3a-methyl-2B,3B-epithio-5a-androstan-17,6-01 17-acetate as crystalsmelting at 133 to 135 C.. 1

[a] +27.2i2 (c.=1.056, 'CHCI3) v IR: part ant- 1727, 1252, 1045, 1031,1020, 976, 932, 913

(G) Preparation of 3a-methyl-Zfl,SB-epithio Sa-androstan-17,8-ol.-Amixture of 3fi-methyl-Zfl-thiocyanato-5aandrostan-3a,17B-ol 17-acetate(0.85 g.) and potassium hydroxide (1.0 g.) in ethanol (3 0 ml.) isstirred at room temperature (10 to 20 C.) overnight. The reactionmixture is combined with water and extracted with dichloromethane. Theextract is crystallized from a mixture of acetone and hexane to give3u-rnethyl-2B,3,8- epithio-5a-androstan-175-01 as crystals melting at to127 C. 7

What is claimed is:

1. 2B-methyl-2a,3a-epithiO-Sa-audrOStan-I75-01.

2. A process for preparing 2 or 3-alkyl-2,3-epithiosteroid having one ofthe general formulae:

S t and Si i H R H wherein R is a hydrogen atom or a lower alkanoylgroup,

R is a lower alkyl group and the ripple mark (3) is a generic indicationof ocand li -configurations, which comprises subjecting a 2- or3-alkyl-A -steroid having one of the general formulae:

I 5 and I Rha each have the same significance as wherein R and Rdesignated above to treatment as follows:

(a) treatment with an. epoxidizing agent in an inert solvent at atemperature from about -10 C. to the boiling point of the solvent usedfor up to a period of from about 1 to hours, or (b) treatment with acombination of a halogenating agent and a base wherein the halogenatingagent is brought into reaction in an inert solvent at a temperature offrom about 0 C. to the boiling point of the solvent used for up to about10 hours and the base is brought into reaction simultaneously with thehalogenating agent or subsequent to the addition of the halogenatingagent in an inert solvent at a tem-. perature of from about roomtemperature to the boiling point of the solvent used for up to about 24hours, subjecting the resultant 2- or 3-alkyl-2,3-epoxysteroid havingone of the general formulae:

and O 1 5 wherein R and R each have the same significance as designatedabove to treatment as follows:

(1) treatment with thiocyanic acid or salt thereof, or (2) treatmentwith thiocyanic acid or salt thereof followed by a halogenation oracylation process, the treatment with thiocyanic acid or salt thereofbeing carried out in an inert solvent at a temperature of from about C.to the boiling point of the solvent used for up to about 5 days, andsubjecting the resultant 2- or 3-alkyl-2- or 3-thiocyanato-steroidhaving one of the general formulae:

on on (13 0O R R x NCS/ NOs-- X-- I n it on on (11 W3 X m- 3 NOS I 2 i RH R H wherein X is a hydroxyl group, a halogen atom, a lower alkanoyloxygroup, a lower alkanesulfonyloxy group, a benzene-sulfonyloxy group or alower alkylbenzenesulfonyloxy group and R and R each have the samesignificance as designated above to treatment as follows:

(1) treatment with a basic agent, or

(ii) treatment with a basic agent followed by an acylation process,

the treatment with the basic agent being carried out in an inert solventat a temperture not higher than C, for up to about 5 days.

References Cited UNITED STATES PATENTS 3,105,831 10/1963 Komeno 260-23953,169,128 2/1965 Komeno 260239.5 3,230,215 1/1966 Komeno 260239.5

OTHER REFERENCES Takeda et a1.: Tetrahedron, vol. 21, February 1965, pp.329-351.

Tori et a1.: Journal Org. Chem, vol. 29, No. 5, May 1964, pp. 1136-1141;

LEWIS GO'ITS, Primary Examiner.

ELBERT L. ROBERTS, Examiner.

JOHNNIE R. BROWN, Assistant Examiner.

1. 2B-METHYL-2A,3A-EPITHIO-5A-ANDROSTAN-17B-OL.